Azasan

CLINICAL PHARMACOLOGY

Azathioprine is well absorbed following oral administration.
Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-azathioprine
and decays with a half-life of 5 hours. This is not an estimate of the half-life
of azathioprine itself but is the decay rate for all 35S-containing metabolites
of the drug. Because of extensive metabolism, only a fraction of the
radioactivity is present as azathioprine. Usual doses produce blood levels of
azathioprine, and of mercaptopurine derived from it, which are

low ( < 1 mcg/mL). Blood levels are of little predictive
value for therapy since the magnitude and duration of clinical effects
correlate with thiopurine nucleotide levels in tissues rather than with plasma
drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable. See OVERDOSAGE.

Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both
compounds are rapidly eliminated from blood and are oxidized or methylated in
erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. Activation of 6-mercaptopurine occurs via
hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of
multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides
(6-TGNs) as major metabolites (See Metabolism Scheme in Figure 1). The
cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN
into DNA.

6-MP undergoes two major inactivation routes (Figure 1). One is thiol methylation,
which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form
the inactive metabolite methyl-6-MP (6-MeMP). TPMT activity is controlled by
a genetic polymorphism.1, 2, 3 For Caucasians and African Americans,
approximately 10% of the population inherit one non-functional TPMT allele (heterozygous)
conferring intermediate TPMT activity, and 0.3% inherit two TPMT non-functional
alleles (homozygous) for low or absent TPMT activity. Non-functional alleles
are less common in Asians. TPMT activity correlates inversely with 6-TGN levels
in erythrocytes and presumably other hematopoietic tissues, since these cells
have negligible xanthine oxidase (involved in the other inactivation pathway)
activities, leaving TPMT methylation as the only inactivation pathway. Patients
with intermediate TPMT activity may be at increased risk of myelotoxicity if
receiving conventional doses of AZASAN® (azathioprine) . Patients with low or absent TPMT
activity are at an increased risk of developing severe, life-threatening myelotoxicity
if receiving conventional doses of AZASAN® (azathioprine) .4-9 TPMT genotyping
or phenotyping (red blood cell TPMT activity) can help identify patients who
are at an increased risk for developing AZASAN® (azathioprine) toxicity.2, 3, 7, 8,
9 Accurate phenotyping (red blood cell TPMT activity) results are not
possible in patients who have received recent blood transfusions. See WARNINGS,
PRECAUTIONS: DRUG INTERACTIONS, PRECAUTIONS:
Laboratory Tests and ADVERSE REACTIONS sections.

Figure 1 : Metabolism pathway of azathioprine: competing
pathways result in inactivation by TPMT or XO, or incorporation of cytotoxic nucleotides into DNA.

Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase
(XO) to form 6-thiouric acid. The inhibition of xanthine oxidase in patients
receiving allopurinol (ZYLOPRIM®) is the basis for the azathioprine dosage
reduction required in these patients (see PRECAUTIONS: DRUG
INTERACTIONS).

Proportions of metabolites are different in individual
patients, and this presumably accounts for variable magnitude and duration of
drug effects. Renal clearance is probably not important in predicting
biological effectiveness or toxicities, although dose reduction is practiced in
patients with poor renal function.

Homograft Survival

The use of azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat
obscure. The drug suppresses hypersensitivities of the cell-mediated type and
causes variable alterations in antibody production. Suppression of T-cell effects, including
ablation of T-cell suppression, is dependent on the temporal relationship to
antigenic stimulus or engraftment. This agent has little effect on established
graft rejections or secondary responses.

Alterations in specific immune responses or immunologic
functions in transplant recipients are difficult to relate specifically to
immunosuppression by azathioprine. These patients have subnormal responses to
vaccines, low numbers of T-cells, and abnormal phagocytosis by peripheral blood
cells, but their mitogenic responses, serum immunoglobulins, and secondary antibody
responses are usually normal.

Immunoinflammatory Response

Azathioprine suppresses disease manifestations as well as
underlying pathology in animal models of autoimmune disease. For example, the
severity of adjuvant arthritis is reduced by azathioprine.

The mechanisms whereby azathioprine affects autoimmune
diseases are not known. Azathioprine is immunosuppressive, delayed
hypersensitivity and cellular cytotoxicity tests being suppressed to a greater
degree than are antibody responses. In the rat model of adjuvant arthritis,
azathioprine has been shown to inhibit the lymph node hyperplasia which
precedes the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose-related. Azathioprine is

considered a slow-acting drug and effects may persist after
the drug has been discontinued.